Vitamin A and its precursor (beta carotene) and synthetic analogs (retinoids) play an important role in the modulation of the growth and differentiation of normal, premalignant, and malignant cells in vivo and in culture. Vitamin A deficiency leads to squamous metaplasia, which can be reversed by vitamin A and by certain retinoids. Interestingly, the metaplasia that develops during vitamin A deficiency is similar to premalignant lesions caused by chemical carcinogens. Dysplastic leukoplakia and erythroplakia are uniquely measurable premalignant lesions that may progress in severity and ultimately result in frank malignancy. We recently completed a controlled, double-blind randomized trial of 13-cis retinoic acid versus placebo in oral leukoplakia. We detected and reported major but reversible activity of 13-cis retinoic acid against oral leukoplakia. Thus, our study strongly indicates that prolonged treatment with 13-cis retinoic acid at a tolerable dose may be necessary to maintain therapeutic effect. We therefore propose a clinical study using an intermediate dose of 13-cis retinoic acid as initial treatment followed by randomization to either low-dose 13-cis retinoic acid as a maintenance treatment or beta carotene as an alternative treatment. We now see more than 50 new patients annually in our institution and will have an additional 30 patients referred from the Dental School. This population will provide invaluable resources for combined clinical and laboratory investigations. During this study we will evaluate the levels of differentiation markers (cholesterol sulfate, involucrin, and transglutaminase) in tissue as biochemical intermediate endpoints and will measure micronuclei reduction as a biological marker, and we will attempt to correlate these markers to treatment. The information we obtain from this study will allow us to develop more rational regimens for the treatment of oral premalignant lesions and to establish a firm approach to chemoprevention of squamous cell carcinoma of the head and neck.